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Abstract BACKGROUND: Prevention and control of disease and injury require information about the leading medical causes of illness and exposures or risk factors. The assessment of the public-health importance of these has been hampered by the lack of common methods to investigate the overall, worldwide burden. The Global Burden of Disease Study (GBD) provides a standardised approach to epidemiological assessment and uses a standard unit, the disability-adjusted life year (DALY), to aid comparisons. METHODS: DALYs for each age-sex group in each GBD region for 107 disorders were calculated, based on the estimates of mortality by cause, incidence, average age of onset, duration, and disability severity. Estimates of the burden and prevalence of exposure in different regions of disorders attributable to malnutrition, poor water supply, sanitation and personal and domestic hygiene, unsafe sex, tobacco use, alcohol, occupation, hypertension, physical inactivity, use of illicit drugs, and air pollution were developed. FINDINGS: Developed regions account for 11.6\% of the worldwide burden from all causes of death and disability, and account for 90.2\% of health expenditure worldwide. Communicable, maternal, perinatal, and nutritional disorders explain 43.9\%; non-communicable causes 40.9\%; injuries 15.1\%; malignant neoplasms 5.1\%; neuropsychiatric conditions 10.5\%; and cardiovascular conditions 9.7\% of DALYs worldwide. The ten leading specific causes of global DALYs are, in descending order, lower respiratory infections, diarrhoeal diseases, perinatal disorders, unipolar major depression, ischaemic heart disease, cerebrovascular disease, tuberculosis, measles, road-traffic accidents, and congenital anomalies. 15.9\% of DALYs worldwide are attributable to childhood malnutrition and 6.8\% to poor water, and sanitation and personal and domestic hygiene. INTERPRETATION: The three leading contributors to the burden of disease are communicable and perinatal disorders affecting children. The substantial burdens of neuropsychiatric disorders and injuries are under-recognised. The epidemiological transition in terms of DALYs has progressed substantially in China, Latin America and the Caribbean, other Asia and islands, and the middle eastern crescent. If the burdens of disability and death are taken into account, our list differs substantially from other lists of the leading causes of death. DALYs provide a common metric to aid meaningful comparison of the burden of risk factors, diseases, and injuries. PIP: The Global Burden of Disease Study used the disability-adjusted life-year (DALY) to compare death and disability from various disorders in developing and developed countries. In 1990, developing countries carried almost 90\% of the global disease burden yet were recipients of only 10\% of global health care funding. The highest disease burdens were in sub-Saharan Africa (21.4\% of global total) and India (20.9\%). Communicable, maternal, perinatal, and nutritional disorders (group 1 causes) predominated in sub-Saharan Africa (65.9\% of burden), while noncommunicable diseases (group 2 causes) accounted for 80\% of the burden in established market economies; injuries (group 3) did not differ substantially across regions. The ratio of group 2 to group 1 disorders can be used as a measure of the epidemiologic transition. Group 2 disorders already surpass group 1 disorders in China, Latin America, and the Caribbean. On a global level, group 1, 2, and 3 causes accounted for 43.9\%, 40.9\%, and 15.1\%, respectively, of DALYs. Overall, the top 3 causes of DALYs in 1990 were lower respiratory infections, diarrheal diseases, and perinatal disorders (low birth weight and birth asphyxia or birth trauma). In developed countries, these causes were ischemic heart disease, unipolar major depression, and cerebrovascular diseases. Malnutrition was the risk factor responsible for the greatest loss of DALYs (15.9\%), followed by poor water supply, sanitation, and personal hygiene (6.8\%).